PROJECT SUMMARY The immune system has enormous power to detect and eliminate pathogens; however, harnessing this power to fight cancer has proven challenging. A major barrier is that CD8 T cells specific for tumor-specific (mutated) proteins and found in tumors are non-responsive and fail to eliminate cancer cells. This non-responsive state has been thought to arise late during tumor development because tumor-specific T cells become ?exhausted? and derailed from their normal effector programming by persistent antigen exposure and/or immunosuppressive microenvironmental factors. Using clinically-relevant genetic cancer mouse models, I recently demonstrated that tumor-specific T cells differentiate to a non-responsive state at the pre-malignant stage, long before the emergence of a pathologically-defined tumor. Thus, T cell non-responsiveness is not necessarily established late during tumorigenesis, but instead already after the initial encounters with tumor antigen. Therefore, to reprogram tumor-specific T cells for cancer immunotherapy, we must look beyond the current framework of tumor-specific T cells as ?exhausted? effectors that need to be re-invigorated and instead design strategies to re-differentiate tumor-specific T cells out of the non-responsive fate to a functional state. In this proposal, I plan to address three critical questions: (1) When and where are tumor-specific T cells fate decisions made? Do signals received during the initial encounter with tumor antigen determine cell fates? (2) How do tumor-specific T cell states in different compartments evolve after tumor resection? Is tumor-specific T cells fate fixed, or can it evolve or change with tumor removal? (3) How can we effectively reprogram tumor- specific T cells for the treatment of solid tumors? To achieve this goal, I propose to (i) map the temporal and spatial factors shaping tumor-specific T cells fate decisions during tumorigenesis (ii) determine the plasticity and chromatin states of tumor-specific T cells in different tissue compartments before and after tumor resection and (iii) use insights gained from stem cell reprogramming studies together with novel epigenome editing technology to re-differentiate tumor-specific T cells that will allow them to effectively control cancer cell growth without inducing excessive immunopathology.